The proposed studies were designed to provide a molecular analysis of structure, organization and polymorphisms of genes within the major histocompatibility complex (MHC) on the short arm of chromosome six (6p) and particularly as they relate to disease states and the normal immune response. Superantigens (bacterial toxins of S. aureus) will be cocrystallized with MHC class II molecules to define how these toxins bind to MHC class II molecules. Gene targeting experiments will be performed to eliminate genes of factor B and the complement component C4 to define further the role of MHC class III molecules in the normal immune response. findings from studies of polymorphisms of MHC molecules will be applied to disease associations, particularly to defining the MHC association of common variable immunodeficiency (CVID). Modern tools of molecular genetics, protein biosynthesis and protein chemistry will be applied to the study of patients, their families and normal families with informative markers on 6p. The overall objective of this project is an understanding of diseases associated with the MHC and the finding of predictive independent markers for these disorders. Thus, more effective and comprehensive diagnosis, genetic counselling and treatment strategies might result.